DESIGN, SYNTHESIS, AND EVALUATION OF SYNTHETIC MIMICS OF CELL SURFACE RECEPTORS

Open Access
Author:
Rummel, Sheryl Ann
Graduate Program:
Chemistry
Degree:
Doctor of Philosophy
Document Type:
Dissertation
Date of Defense:
August 01, 2008
Committee Members:
  • Blake R Peterson, Committee Chair
  • Scott T Phillips, Committee Member
  • Philip C. Bevilacqua, Committee Member
  • Avery August, Committee Member
Keywords:
  • synthetic receptors
  • VEGF
  • calixarene
  • vancomycin
Abstract:
The plasma membrane of mammalian cells is composed of a vast array of lipids and proteins arranged in a lipid bilayer. Many of these proteins function as receptors and facilitate or control cell signaling events. In addition, some receptors mediate the uptake of specific ligands from the surrounding environment. These receptors include at least three regions: an extracellular ligand binding motif, a linker region, and a membrane-binding domain. These receptors can also have an internal cytoplasmic region. The extracellular domains can be targeted to deliver drugs or macromolecules to the intracellular environment through receptor-mediated endocytosis. We constructed artificial cell surface receptors that comprise an outward-projecting ligand binding domain, a linker region, and the membrane anchor N-alkyl-3â-cholesterylamine. These artificial receptors mimic trafficking and membrane association properties of endogenous cholesterol by inserting into the plasma membranes of living mammalian cells and cycling between the cell surface and endosomal compartments. We report here that calix[4]arene scaffolds linked to a cholesterylamine anchor can be used to effect the intracellular delivery of vascular endothelial growth factor (VEGF), a growth factor that plays key roles in cancer proliferation. We further report the effective delivery of both monomeric and dimeric versions of the drug vancomycin into mammalian cells using the ligand-binding peptide D-Phe-D-Ala, enabling eradication of intracellular bacteria. Synthetic cell surface receptors represent promising tools for drug delivery, novel cellular probes, and innovative modulators of biological systems.